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首页> 外文期刊>BioResearch open access. >Deficiency in MyD88 Signaling Results in Decreased Antibody Responses to an Adeno-Associated Virus Vector in Murine Pompe Disease
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Deficiency in MyD88 Signaling Results in Decreased Antibody Responses to an Adeno-Associated Virus Vector in Murine Pompe Disease

机译：MyD88信号的不足导致对鼠庞贝病中与腺相关病毒载体的抗体应答降低

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We have previously shown that antibody and T cell responses limit the efficacy of an adeno-associated virus (AAV) pseudotype 8 (2/8) vector containing the universally active cytomegalovirus enhancer/chicken β-actin regulatory cassette (AAV2/8-CBhGAA) in treating murine Pompe disease. However, the innate immune responses to AAV2/8-CBhGAA are largely unknown. In this study, we investigated acute immune responses to AAV2/8-CBhGAA and the role of MyD88/TRIF signaling pathway in shaping adaptive immune responses to this vector. We showed here that a small and transient increase in CXCL-1 and IL-1β expression in livers of acid-α-glucosidase knockout (GAAKO) mice 6?h following injection with AAV2/8-CBhGAA. There was a robust antibody response to GAA in wild-type mice injected with this vector. In contrast, the anti-GAA IgG1 response was diminished in MyD88KO mice, and showed a trend toward a decrease in TRIFKO mice. In addition, the vector genome and GAA activity were significantly higher in MyD88KO livers compared with wild-type livers, suggesting reduced cytotoxic T cell responses. Importantly, elevated CD4+ T cells were detected by immunohistochemistry in MyD88KO livers. When adoptively transferred to wild-type mice, these CD4+ T cells have an ability to suppress antibody responses against AAV2/8-CBhGAA and to prevent further immunization against rhGAA. Our study suggests that the MyD88 deficiency leads to the suppression of deleterious immune responses to AAV2/8-CBhGAA, which has implications for gene therapy in Pompe disease.
机译：先前我们已经证明，抗体和T细胞反应会限制包含通用活性巨细胞病毒增强剂/鸡β-肌动蛋白调节盒（AAV2 / 8-CBhGAA）的​​腺相关病毒（AAV）假型8（2/8）载体的功效在治疗鼠庞贝病中。但是，对AAV2 / 8-CBhGAA的先天免疫应答在很大程度上是未知的。在这项研究中，我们调查了对AAV2 / 8-CBhGAA的急性免疫反应以及MyD88 / TRIF信号通路在塑造对该载体的适应性免疫反应中的作用。我们在这里显示，注射AAV2 / 8-CBhGAA后6？h，酸性-α-葡萄糖苷酶敲除（GAAKO）小鼠肝脏中CXCL-1和IL-1β表达的短暂而短暂的增加。在注射该载体的野生型小鼠中，GAA有很强的抗体反应。相比之下，在MyD88KO小鼠中，抗GAA IgG1应答减弱，并且在TRIFKO小鼠中呈下降趋势。此外，与野生型肝脏相比，MyD88KO肝脏中的载体基因组和GAA活性显着更高，表明细胞毒性T细胞反应降低。重要的是，通过免疫组织化学在MyD88KO肝脏中检测到CD4 + T细胞升高。这些CD4 + T细胞过继转移到野生型小鼠后，具有抑制针对AAV2 / 8-CBhGAA的抗体反应并阻止进一步针对rhGAA免疫的能力。我们的研究表明，MyD88缺乏导致对AAV2 / 8-CBhGAA的有害免疫反应的抑制，这对庞贝病的基因治疗具有重要意义。

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